We are performing a genome wide search to identify chromosome regions likely to contain genes that cause bipolar affective disorder (manic depressive illness). One percent of the population is afflicted by this severe cyclical mood disorder, making it one of the most common of the severe mental disorders, and a major public health problem. Moreover, unrecognized or untreated patients with bipolar affective disorder have an approximately 20% risk of death from suicide. We have carried out a systematic genome wide search for genes responsible for bipolar affective disorder in an Old Order Amish kindred of Southeastern Pennsylvania. Although the Old Order Amish generally have the same prevalence of bipolar affective disorder as other populations, for our genetic studies we have utilized several very large extended Amish families where there is an extremely high incidence of bipolar affective disorder over several generations. Large families from a closed population like the Old Order Amish are valuable because they have a reduced number of genes contributing to the illness and we are able to track the illness through the generations. Each gene should also have a larger effect, making them easier to detect. For complex diseases like bipolar affective disorder, each of several genes may increase an individual's susceptibility to develop the disease but any one gene by itself may not be sufficient to cause the full severity of the illness. In studying large numbers of individuals from the general population this presents a very difficult statistical problem since it is likely that different genes cause the illness in different families. Our results suggest that genes on chromosomes 6, 13, and 15, rather than just a single gene, have roles in determining the susceptibility to and severity of bipolar affective disorder. Although the genes causing bipolar affective disorder in the Old Order Amish may also cause illness among non-Amish, it is likely that additional sets of genes are also involved in the susceptibility to develop bipolar affective disorder in other populations.